COMMUNICATIONS doi.org/10.1002/adsc.

202101016

Ligand-Controlled, Tunable Copper-Catalyzed Radical Divergent

Trifluoromethylation of Unactivated Cycloalkenes
Qi Wang,a Zhong-Lin Zang,a,* Mi Jie,a Li-Hua Luo,a Dan Yang,a
Cheng-He Zhou,a and Gui-Xin Caia,*
a
Institute of Bioorganic & Medicinal Chemistry, Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of
Education, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715 (People’s Republic of
China)
E-mail: zhonglinzang@swu.edu.cn; gxcai@swu.edu.cn

Manuscript received: August 18, 2021; Revised manuscript received: October 2, 2021;
Version of record online: October 22, 2021

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202101016

Abstract: The Cu-catalyzed high-chemoselective ylating reagents such as the Umemoto,[6] Togni,[7]
trifluoromethylation reactions of unactivated cyclo- Langlois reagents[8] and (trifluoromethyl)
alkenes via the modulation of appropriate ligands trimethylsilane[9] to afford the CF3 source. There is no
have been explored. The Cu(I)/appropriate ligands- doubt that the trifluoromethylation of olefin with
catalytic systems overcome the key challenge in concomitant introduction of other functional groups
differentiating two pathways involving radical inter- into molecular scaffolds is one of extremely efficient
mediates and provide a ligand-controlled approach and economical methods[10] such as oxytrifluorometh-
for site-specific spiro-aryltrifluoromethylation and ylation,[11] aminotrifluoromethylation,[12] carbo-
chlorotrifluoromethylation to afford trifluorometh- trifluoromethylation,[13] thiotrifluoromethylation[14] and
ylated spiro-tetrahydroquinoline compounds and halotrifluoromethylation.[15] Regarding vicinal
vicinal Cl-containing trifluoromethyl cycloalkanes. trifluoromethylated difunctionalization of alkene reac-
Moreover, compared with reported chlorine sources, tions, the construction of trifluoromethylated spiro-
1,2-dichloroethane is used as more green and cycle via carbotrifluoromethylation reaction was rarely
economical feedstock for chlorotrifluorometh- reported,[13a–f] but on the other hand,
ylation. chlorotrifluoromethylation was generally realized by
extremely active chlorine sources, for instance,
CF3SO2Cl,[15a–f] TMS Cl[15h] and dichloride
[15i]
Keywords: ligand effects; fluorine; cyclization; sulfoxide as well as equivalent CuCl.[15g] We
chlorine; synthetic methods hypothesize that, if carbotrifluoromethylation and
chlorotrifluoromethylation involving radical intermedi-

The trifluoromethyl group (CF3 ) is highly important

in pharmaceuticals because of their abundance in
numerous fluorinated drugs aiming to improve chem-
ical and metabolic stability, enhance bioavailability
and lipophilicity as well as the protein bind affinity.
For example, the trifluoromethylated moiety represents Figure 1. Pharmaceutically important trifluoromethylated mole-
an important pharmacophore in fluorinated drugs and cules.
other bioactive compounds (Figure 1).[1]
Considerable attention has been devoted toward the
development of versatile approaches for introducing ates can be regulated in the similar catalytic system,
the CF3 group into various organic frameworks.[2] In divergent trifluoromethylation reactions should be
recent years, the trifluoromethylation of alkenes have easily available. However, it is a well-known fact that
been reported by using thermodynamical transition radical intermediates are extremely active and gener-
metal catalysis,[3] photocatalysts[4] and electrochemical ally uncontrollable, and therefore it is an attractive and
oxidation[5] simultaneously utilizing trifluorometh- interesting challenge to control the selectivity in

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 COMMUNICATIONS asc.wiley-vch.de

radical reactions.[16] Despite recently remarkable radi- Table 1. Optimization of the reaction conditions.[a]
cal transformation to form desired products with high
stereoselectivity,[4e,17] the development of general strat-
egies to tune the selectivity of radical reactions remains
underdeveloped. The strategy for forging new bonds
with higher levels of chemo-diversity from the identi- Entry Ligand (eq.) Togni reagent (eq.) T Yield (%)[b]
cal reactant provides promising synthetic tools in (°C) 1 a 2 a 3 a
synthetic chemistry. Thus, tuning the chemo-selectivity
of a radical reaction by ligand-controlled manner[18] 1[c] Dppe (0.15) 1.8 110 3 45 7
has been attracting more and more attention. In 2[c] Dppe (0.3) 1.8 110 7 38 7
addition, the chlorotrifluoromethylated reaction using 3 Dppe (0.3) 1.8 110 7 27 13
4 TMG (0.3) 1.8 110 7 38 6
above chlorination agents is not convenient and
5 2-PA (0.3) 1.8 110 10 44 37
economical, and there is an urgent need for more green 6 2-PA (0.3) 1.8 100 5 37 13
and economical chlorine sources. 7 2-PA (0.3) 2.0 100 0 46 17
Herein, overcoming extremely active allylic 8 2-PA (0.3) 1.6 100 0 42 18
trifluoromethylation,[19] we report ligand-controlled 9 2-PA (0.3) 1.4 100 2 41 7
high-chemoselective trifluoromethylation reactions of 10 2-PA (0.3) 1.2 100 13 72 14
unactivated cycloalkenes via copper catalysis. It is 11[d] 2-PA (0.3) 1.2 100 16 10 19
worth noting that this radical transformation based on 12 Bipy (0.3) 1.2 100 28 6 39
ligand regulation can undergo intramolecular 13 Bipy (0.3) 1.2 110 22 30 19
aryltrifluoromethylation to form trifluoromethylated 14 DMphen (0.3) 1.2 110 13 21 52
spiro-tetrahydroquinolines and intermolecular 15 DMphen (0.3) 1.4 110 17 9 49
chlorotrifluoromethylation utilizing 1,2-dichloro- 16 DMphen (0.3) 1.6 110 22 12 41
ethane (DCE) as an available and economical chlorine 17 DMphen (0.3) 1.8 110 10 13 72
18 DMphen (0.3) 2.0 110 3 19 54
source (Scheme 1).
19[d] DMphen (0.3) 1.8 110 32 23 41
Our initial studies focused on the screening of 20[d] None 1.2 100 16 13 27
ligands using N-(2-(cyclohex-1-en-1-yl) ethyl)-N-
[a]
phenyl-4-(trifluoromethyl)benzenesulfonamide (1 a), Reaction conditions: 1 a (0.1 mmol), Togni reagent, CuCl
copper catalyst and Togni reagent as model reaction to (0.01 mmol), Ligand (0.03 mmol), 1,2-Dichloroethane
explore the optimal reaction conditions of (DCE) (2 mL) in a sealed tube, under Ar atmosphere, 20–
trifluoromethylated spiro-tetrahydroquinoline deriva- 24 h. 1,2-Bis-(diphenylphosphine)ethane = Dppe, Tetrameth-
tive 2 a and α-chloro-β-trifluoromethylated product 3 a, ylguanidine = TMG, 2,2’-Bipyridine = Bipy, 4,7-Dimethyl-
1,10-phenanthroline = DMphen.
respectively (Table 1). From the screening of ligands [b]
Yield of 1 a was the recovered starting material by isolated
(Table 1, entries 1–5), 2-picolinamide (2-PA) gave operation; yields of 2 a and 3 a were isolated yields based on
better performance, producing desired product 2 a in invested starting materials.
44% isolated yield and 37% yield of 3 a with 10% of [c]
CuI instead of CuCl.
recovered 1 a at 110 °C (Table 1, entry 5). Decreasing [d]
without CuCl.
the reaction temperature to 100 °C showed that the
selectivity of 2 a and 3 a was obviously increased and
the recovered yield of 1 a was reduced to 5% (Table 1, ylated spiro product 2 a in 72% isolated yield at 100 °C
entry 6). Further investigations on the equivalent of with high chemoselectivity (Table 1, entry 10). The
Togni reagent (Table 1, entries 7–10) disclosed that absence of CuCl led to poor performance (Table 1,
1.2 equiv. of Togni reagent gave rise to trifluorometh- entry 11). Then we switched to improve the yield of
3 a. When 2,2’-bipyridine (Bipy) was applied, the α-
chloro-β-trifluoromethylation of 1 a took place with
comparably high chemoselectivity for 3 a while the
recovered yield of 1 a was relative high (Table 1,
entry 12). To promote the transformation of 1 a, the
reaction temperature was increased to 110 °C and the
chemoselectivity for 3 a dropped (Table 1, entry 13).
Notably, utilizing 4,7-dimethyl-1,10-phenanthroline
(DMphen) as ligand enhanced the reaction efficiency
and chemoselectivity for 3 a (Table 1, entry 14). Fur-
ther investigations on the equivalent of Togni reagent
Scheme 1. Ligand-controlled radical spiro-aryltrifluorometh- (Table 1, entries 15–18) demonstrated that 1.8 equiv. of
ylation and chlorotrifluoromethylation of unactivated cyclo- Togni reagent was optimal, affording 3 a in 72%
alkenes. isolated yield (Table 1, entry 17). The cooperation of

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 COMMUNICATIONS
catalyst and ligand gave the best result (Table 1,
entries 19–20). Moreover, N-(2-(cyclohex-1-en-1-yl)
ethyl) aniline substrates with different N-protecting
groups (1 p–1 w) were examined. Further screening
reaction conditions are shown in the Supporting
Information Table S2 and Table S4.
Having established optimized spiro-aryltrifluoro-
methylation reaction conditions, we next examined the
scope of this reaction (Table 2). Substrates bearing six-
and five-cyclic olefins proceeded smoothly to give
corresponding products (2 a–2 b), in which the struc-
ture of product 2 a was determined by X-ray
analysis.[20] However, cycloheptene substrate per-
Table 2. Scope of the spiro-aryltrifluoromethylation reaction.[a]
[a]
Reaction conditions I: 1 (0.1–0.3 mmol, 1 eq.), Togni
reagent (1.2 eq.), CuCl (0.1 eq.), 2-picolinamide (0.3 eq.),
DCE (2 mL) in a sealed tube, under Ar atmosphere, 100 °C,
20–36 h. All yields were isolated yields, and the yield in
bracket was starting material recovered.
[b]
3 c was obtained in 27% isolated yield (1 c: 30%).
Adv. Synth. Catal. 2021, 363, 5284 – 5291
asc.wiley-vch.de
formed badly with a trace of product 2 c. A substrate
with a para-methyl substituent on cyclohexenyl group
was converted into 2 d in 46% isolated yield. A variety
of anilines substrates were next evaluated. The sub-
strates bearing electron-donating groups (methyl and
methoxy) afforded the desired products 2 e, 2 g–2 h in
42–47% isolated yields, while only a trace of ortho-
substituted product 2 f was obtained, probably for steric
effect reasons. Substrates containing electron-with-
drawing groups (halides, acetyl and ester) on the
phenyl rings were tolerated and furnished the corre-
sponding products 2 i–2 l in 35–61% isolated yields.
The β-naphthylamine derivative was converted to
trifluoromethylated spirocyclic product 2 m in 39%
isolated yield. This reaction could be also applied to
construct trifluoromethylated spiro-dihydroindole
product 2 n in 48% isolated yield. The introduction of
allyl group to the substrate led to linear allylic
hydrotrifluoromethylated product 2 o, which meant that
linear olefin is more active than cycloalkene. Sub-
strates with other N-protecting groups such as p-Ts, p-
TsNO2 and Boc groups also afforded the corresponding
products 2 p–2 r in 71%, 15% and 72% isolated yields,
respectively. By enlarging the scale of template
reaction to 10 times, product 2 a can be obtained in
66% isolated yield, and 19% of starting material 1 a
was recovered.
The substrate scope of the vicinal chlorotrifluoro-
methylation was also investigated (Table 3). Substrates
bearing six-, five- and seven-membered cyclic olefins
gave corresponding products (3 a–3 c) in 58–72%
isolated yields. A substrate with a para-methyl sub-
stituent on cyclohexenyl group delivered 3 d in 75%
isolated yield. A variety of anilines substrates bearing
electron-donating on the phenyl rings afforded the
desired products 3 e–3 h in 25–63% isolated yields and
these results showed that the position of the substituent
has a significant influence on the yield. Besides,
substrates with electron-withdrawing substituents on
the phenyl rings gave the desired products 3 i–3 l in
47–59% isolated yields. The electron effects of the
substituents have no obvious influence. Regretfully,
the β-naphthylamine derivative was not tolerated and
only cyclized product 2 m was obtained under this
condition without chlorotrifluoromethylated product
3 m. A similar situation was found in cyclohex-1-en-1-
ylmethanamine derivative substrate and chlorotri-
fluoromethylated product 3 n was not detected. The
presence of the allyl group in the substrate afforded
chlorotrifluoromethylated product 3 o, meaning that
linear olefin remained more active for this trans-
formation. Substrates with other N-protecting groups
such as p-Ts and p-TsNO2 groups also gave corre-
sponding the products 3 p and 3 q in 61% and 31%
isolated yields respectively, while the N-Boc product
3 r was not obtained. To demonstrate the utility of this
methodology, the scale of template reaction was
5286 © 2021 Wiley-VCH GmbH
 COMMUNICATIONS asc.wiley-vch.de

Table 3. Scope of the vicinal chlorotrifluoromethylation reac-

tion.[a]

Scheme 2. Mechanism studies for spiro-aryltrifluorometh-

ylation and chlorotrifluoromethylation.

[a]
Reaction conditions II: 1 (0.1–0.3 mmol, 1 eq.), Togni
reagent (1.8 eq.), CuCl (0.1 eq.), DMPhen (0.3 eq.), DCE
(2 mL) in a sealed tube, under Ar atmosphere, 110 °C, 20–
36 h. Yields of isolated products after purification by column
chromatography on silica gel are given.
[b]
The yield in bracket was starting material recovered.
[c]
2 m was obtained in 23% isolated yield.
[d]
2 n was obtained in 23% isolated yield.

enlarged to 10 times, product 3 a can be obtained with

a yield of 62%, and 19% of starting material 1 a was
recovered.
To further gain insight into the reaction mechanism,
control experiments were conducted under required
conditions (Schemes 2 and 3). 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) serving as radical scavenger
was used under reaction conditions I and II, respec-
tively, and desired products 2 a and 3 a were not
detected (Scheme 2, Eq. 1 and Eq. 2). These results
supported the radical pathways in this transformation.
Subjecting 3 a to required conditions cannot provide
trifluoromethylated spiro-tetrahydroquinoline com-
pound 2 a (Scheme 2, Eq. 3); this result suggests that
the transformation of 3 a to 2 a is unlikely because 2 a
and 3 a followed different pathways.
Scheme 3. Deuteration experiments for spiro-aryltrifluorometh-
ylation and chlorotrifluoromethylation.
The kinetic isotope effect (KIE) experiments were
carried out for the spiro-aryltrifluoromethylation reac-
tion, which underwent intramolecular spirocyclization
of olefins via the cleavage of the Csp2 H bond of the
benzene ring (Scheme 3, Eq. 1 to Eq. 3). The KIE (kH/
kD = 1.5) measured in parallel experiments and the KIE
(kH/kD = 1.0) measured in intermolecular competition
experiment indicated that the pheny Csp2 H bond
cleavage step might not be the turnover-limiting step.

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 COMMUNICATIONS asc.wiley-vch.de

The experiments using D2O showed that deuterium of new compound I, Togni reagent reacted in the
incorporation was not detected, respectively presence of DCE with the variations of CuCl and
(Scheme 3, Eq. 4 and Eq. 5). ligands (Table 4B). These experimental results showed
We next conducted the research of intermediate I that the cooperation of CuCl and DMPhen ligand
and chlorine source (Table 4 and 5). The reaction of 1 f activates Togni reagent and DCE, leading to new
under reaction conditions II proceeded smoothly to compound I. Furthermore, different solvents under
give desired product 3 f with concomitant new com- revised reaction conditions II were tested to explore
pound I (Table 4A), which meant that DCE might be the source of chlorine (Table 5). Screening solvents
the chlorine source. To gain insight into the formation experiments illustrated that organic Cl-containing
solvents such as CHCl3 and DCM facilitated this
transformation and provided the chlorine source.
Table 4. Exploration of intermediate I. However, inorganic chlorine source such as nBu4NCl
failed in promoting this transformation. All above
observations gave supportive evidence that DCE is the
optimal chlorine source.[15j]
A mechanistic rationale involving two pathways is
outlined (Scheme 4).[19b,21] In path a, Cu(I)Cl assisted
by 2-picolinamide LA catalytically activates Togni
reagent to afford a CF3 radical and Cu(II) species.
Atom transfer radical addition (ATRA) of a CF3 radical
to 1 a gives rise to trifluoromethylated radical inter-
mediate II, which cyclizes to the aromatic ring in the
presence of Cu(II) species and LA to generate spiro
Entry Variations Intermediate I (%)[a] Cu(III) species III. Reductive elimination from the
spiro Cu(III) species III gives trifluoro-methylated
1 CuCl, DMphen 41
2 DMphen 0
spiro-tetrahydroquinoline 2 a and regenerates Cu(I)
3 CuCl 0
4 – 0
5 2-PA 0
6 CuCl, 2-PA 0
[a]
Reaction conditions: Togni reagent (0.18 mmol), CuCl
(0.01 mmol), DMphen (0.03 mmol), DCE (2 mL) in a sealed
tube, under Ar atmosphere, 110 °C (or 2-PA (0.03 mmol),
100 °C) 14 h. The yield was obtained by silica gel column
chromatography.

Table 5. Exploration of chlorine source.

Entry Variations Yield (%)[a]

1a 2a 3a
1 CHCl3 7 6 37
2 DCM 32 8 29
3 CCl4 N.D.[b] 0 0
4 CH3CN N.D.[b] 0 0
5 DMF[c] N.D.[b] 0 0
[a]
Revised reaction conditions II: 1 a (0.1 mmol), Togni reagent
(0.18 mmol), CuCl (0.01 mmol), DMphen (0.03 mmol),
solvent (2 mL) in a sealed tube, under Ar atmosphere,
110 °C, 23 h. All yields were isolated yields. DCM =
Dichloromethane.
[b]
N.D. = Not detected.
[c] n
Bu4NCl (0.11 mmol) was added. Scheme 4. Mechanistic rationale.

Adv. Synth. Catal. 2021, 363, 5284 – 5291 5288 © 2021 Wiley-VCH GmbH
 COMMUNICATIONS
species. In path b, similarly, trifluoromethylated radical
intermediate II is formed, which can be further
oxidized to the carbocation intermediate IV in the
presence of Cu(II) species and DMphen LB. Simulta-
neously, the cooperation of CuCl and LB activates
Togni reagent and DCE, leading to new compound I,
which provides the chlorine source for the carbocation
intermediate IV, releasing vicinal Cl-containing
trifluoromethyl cycloalkane 3 a. Ligand LB has a more
rigid skeleton which is unfavourable for the formation
of the intermediate III. Therefore, ligand LB binds to
[Cu] in a bidentate manner and actively participates in
chlorotrifluoromethylation and ligand LA serving as a
bidentate ligand promotes spiro-aryltrifluorometh-
ylation.
In summary, a novel and straightforward ligand-
regulated strategy for the trifluoromethyl spiro-dihy-
droquinoline products and chlorotrifluoromethyl prod-
ucts in cyclic olefins system has been developed using
Cu(I) catalysis. Deuteration experiments and relative
mechanism studies suggested that different radical
pathways might be involved in spiro-aryltrifluorometh-
ylation and chlorotrifluoromethylation. The high che-
moselective difunctional methodology of cyclic olefins
provides a powerful tool in radical transformations and
makes practical applications. Efforts toward the devel-
opment asymmetric trifluoromethylated reaction as
well as applications of this methodologies in the
synthesis of biological products are ongoing in our
laboratory.
Experimental Section
General Procedure for the Spiro-Aryltrifluorometh-
ylation Reaction
CuCl (0.1 eq.), 2-picolinamide (0.3 eq.), Togni reagent (1.2 eq.),
substrates 1 (0.1 ~ 0.3 mmol, 1.0 eq.) and DCE (2.0 ~ 6.0 mL)
were put into oven-dried tubes (15 mL) under an argon
atmosphere. The mixtures was stirred at 100 °C for 20–36 hours.
And the progress of this reaction was monitored by TLC. After
the reaction system was cooled to room temperature, the
resultant was purified directly by silica gel column chromatog-
raphy (petroleum ether/EtOAc = 80:1 ~ 50:1) to give the prod-
ucts 2.
General Procedure for the Chlorotrifluorometh-
ylation Reactions
CuCl (0.1 eq.), 4,7-dimethyl-1,10-phenanthroline (DMphen
0.3 eq.), Togni reagent (1.8 eq.), substrates 1 (0.1 ~ 0.3 mmol,
1.0 eq.) and DCE (2.0 ~ 6.0 mL) were put into oven-dried tubes
(15 mL) under an argon atmosphere. The mixtures was stirred
at 110 °C for 20–36 hours. And the progress of this reaction was
monitored by TLC. After the reaction system was cooled to
room temperature, the resultant was purified directly by silica
gel column chromatography (petroleum ether/EtOAc = 80:1 ~
50:1) to give the products 3.
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asc.wiley-vch.de
Acknowledgements
We are grateful to the Research Funds for the Central
Universities (XDJK2018C040), the Doctoral Fund of Southwest
University (SWU117056) and Natural Science Foundation of
Chongqing (cstc2019jcyj-msxmX0437) for the support of this
research. We sincerely thank Dr. Zhi-Peng Wang (Chongqing
Institute of Green and Intelligent Technology, Chinese Academy
of Sciences) for the HPLC analysis.
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